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Severe cholestatic hepatitis due to temozolomide: an adverse drug effect to keep in mind. Case report and review of literature.

Grieco A, Tafuri MA, Biolato M, Diletto B, Di Napoli N, Balducci N, Vecchio FM, Miele L - Medicine (Baltimore) (2015)

Bottom Line: Temozolomide is the current standard of therapy for postoperative patients with glioblastoma starting adjuvant radiotherapy.Hematologic adverse events are the most frequent side effects of temozolomide, while liver toxicity has been reported only in the post-marketing period.In conclusion, a close monitoring of liver function tests is recommended during treatment with temozolomide.

View Article: PubMed Central - PubMed

Affiliation: From the Institute of Internal Medicine, Catholic University of Rome (AG, MB, LM); Institute of Radiotherapy, Catholic University of Rome (MAT, BD, NDN, NB); and Institute of Pathology, Catholic University of Rome (FMV).

ABSTRACT
Temozolomide is the current standard of therapy for postoperative patients with glioblastoma starting adjuvant radiotherapy. Hematologic adverse events are the most frequent side effects of temozolomide, while liver toxicity has been reported only in the post-marketing period. Here we report a case of severe temozolomide-induced liver injury during concurrent radiotherapy treatment, at a dose level of 75 mg/m2. The aim of this case report is to focus on the problems of temozolomide-induced hepatotoxicity. In conclusion, a close monitoring of liver function tests is recommended during treatment with temozolomide.

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Related in: MedlinePlus

Liver function tests of the patient during the treatment course.
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Figure 1: Liver function tests of the patient during the treatment course.

Mentions: A 67-year-old man with no previous medical history was admitted in neurology clinic at “Gemelli” Hospital on May 2012 because of gait disturbance and face perceptual deficit (prosopagnosia). Cranial gadolinium– enhanced magnetic resonance imaging showed a lesion suspected to be a primary malignant brain tumor in the right temporo-parietal-occipital lobe. The patient underwent right fronto-temporal-parietal craniotomy and excision of the lesion. In adherence to the neurosurgery protocol, he started postoperative antiedema treatment with dexamethasone (4 mg twice daily) and esomeprazole (40 mg once a day). The histological report confirmed the diagnosis of glioblastoma multiforme. On day 41 after resection the patient started adjuvant combined chemoradiotherapy, based on 60 Gy (2 Gy per fraction) with concomitant oral temozolomide 75 mg/m2/day according to current guidelines.1 Baseline laboratory workup was unremarkable with normal blood cell count and normal liver function tests. One month later, the patient was hospitalized due to severe asthenia and jaundice. On admission, laboratory test results showed severe cholestatic hepatitis: alanine aminotransferase (ALT) 1128 IU/L; serum total bilirubin 7,96 mg/dL; conjugated bilirubin 5.75 mg/dL; γ-glutamyltransferase (GGT) 1325 IU/L; alkaline phosphatase 458 IU/L; prothrombin time 98%, platelets 202 × 109/L, WBC 10.79 × 109/L, creatinine 0.78 mg/dL. Viral (hepatitis B, hepatitis C, hepatitis A, cytomegalovirus, Epstein–Barr virus, rubella virus, herpes virus) and autoimmune etiologies were excluded. Abdominal ultrasound and computed tomography examination did not reveal pathological findings. A chart of the liver function test levels is reported in Figure 1. Temozolomide was suspended. The patient started ursodeoxycholic acid 300 mg TID po, ademetionine 400 mg BID i.v., methylprednisolone 40 mg QD i.v., and multielectrolyte solution in 5% dextrose 2000 mL QD i.v. Unfortunately, liver function did not improve and total bilirubin level rose to 25.28 mg/dL, ALT to 2322 UI/L, GGT to 2074 UI/L, and alkaline phosphatase to 780 IU/L. Liver biopsy was performed. Histological examination showed severe centrilobular and canalicular cholestasis with preserved hepatic architecture. The findings were considered consistent with toxic liver injury (Figure 2). Three weeks after admission, despite slow progressive improvement of all liver function tests, the patient's general conditions worsened and he died of Staphylococcus aureus sepsis 30 days after admission.


Severe cholestatic hepatitis due to temozolomide: an adverse drug effect to keep in mind. Case report and review of literature.

Grieco A, Tafuri MA, Biolato M, Diletto B, Di Napoli N, Balducci N, Vecchio FM, Miele L - Medicine (Baltimore) (2015)

Liver function tests of the patient during the treatment course.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4554001&req=5

Figure 1: Liver function tests of the patient during the treatment course.
Mentions: A 67-year-old man with no previous medical history was admitted in neurology clinic at “Gemelli” Hospital on May 2012 because of gait disturbance and face perceptual deficit (prosopagnosia). Cranial gadolinium– enhanced magnetic resonance imaging showed a lesion suspected to be a primary malignant brain tumor in the right temporo-parietal-occipital lobe. The patient underwent right fronto-temporal-parietal craniotomy and excision of the lesion. In adherence to the neurosurgery protocol, he started postoperative antiedema treatment with dexamethasone (4 mg twice daily) and esomeprazole (40 mg once a day). The histological report confirmed the diagnosis of glioblastoma multiforme. On day 41 after resection the patient started adjuvant combined chemoradiotherapy, based on 60 Gy (2 Gy per fraction) with concomitant oral temozolomide 75 mg/m2/day according to current guidelines.1 Baseline laboratory workup was unremarkable with normal blood cell count and normal liver function tests. One month later, the patient was hospitalized due to severe asthenia and jaundice. On admission, laboratory test results showed severe cholestatic hepatitis: alanine aminotransferase (ALT) 1128 IU/L; serum total bilirubin 7,96 mg/dL; conjugated bilirubin 5.75 mg/dL; γ-glutamyltransferase (GGT) 1325 IU/L; alkaline phosphatase 458 IU/L; prothrombin time 98%, platelets 202 × 109/L, WBC 10.79 × 109/L, creatinine 0.78 mg/dL. Viral (hepatitis B, hepatitis C, hepatitis A, cytomegalovirus, Epstein–Barr virus, rubella virus, herpes virus) and autoimmune etiologies were excluded. Abdominal ultrasound and computed tomography examination did not reveal pathological findings. A chart of the liver function test levels is reported in Figure 1. Temozolomide was suspended. The patient started ursodeoxycholic acid 300 mg TID po, ademetionine 400 mg BID i.v., methylprednisolone 40 mg QD i.v., and multielectrolyte solution in 5% dextrose 2000 mL QD i.v. Unfortunately, liver function did not improve and total bilirubin level rose to 25.28 mg/dL, ALT to 2322 UI/L, GGT to 2074 UI/L, and alkaline phosphatase to 780 IU/L. Liver biopsy was performed. Histological examination showed severe centrilobular and canalicular cholestasis with preserved hepatic architecture. The findings were considered consistent with toxic liver injury (Figure 2). Three weeks after admission, despite slow progressive improvement of all liver function tests, the patient's general conditions worsened and he died of Staphylococcus aureus sepsis 30 days after admission.

Bottom Line: Temozolomide is the current standard of therapy for postoperative patients with glioblastoma starting adjuvant radiotherapy.Hematologic adverse events are the most frequent side effects of temozolomide, while liver toxicity has been reported only in the post-marketing period.In conclusion, a close monitoring of liver function tests is recommended during treatment with temozolomide.

View Article: PubMed Central - PubMed

Affiliation: From the Institute of Internal Medicine, Catholic University of Rome (AG, MB, LM); Institute of Radiotherapy, Catholic University of Rome (MAT, BD, NDN, NB); and Institute of Pathology, Catholic University of Rome (FMV).

ABSTRACT
Temozolomide is the current standard of therapy for postoperative patients with glioblastoma starting adjuvant radiotherapy. Hematologic adverse events are the most frequent side effects of temozolomide, while liver toxicity has been reported only in the post-marketing period. Here we report a case of severe temozolomide-induced liver injury during concurrent radiotherapy treatment, at a dose level of 75 mg/m2. The aim of this case report is to focus on the problems of temozolomide-induced hepatotoxicity. In conclusion, a close monitoring of liver function tests is recommended during treatment with temozolomide.

Show MeSH
Related in: MedlinePlus